title: Chediak-Higashi syndrome: description of two novel homozygous missense mutations causing divergent clinical phenotype.
abstract: Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease resulting from mutations in the LYST/CHS1 gene, which encodes for a 429 kDa protein, CHS1/LYST, that regulates vesicle trafficking and determines the size of lysosomes and other organelles. To date, 60 different mutations have been characterized, and a reasonably straightforward phenotype-genotype correlation has been suggested. We describe two patients on opposite ends of the CHS clinical spectrum with novel missense mutations. We characterized these patients in terms of their mutations, protein localization and expression, mRNA stability, and electrostatic potential. Patient 1 is the first report of a severe early-onset CHS with a homozygous missense mutation (c.11362 G>A, p.G3725R) in the LYST/CHS1 gene. This molecular change results in a reduction at the CHS1 protein level, not due to an mRNA effect, but maybe a consequence of both, a change in the structure of the protein and most likely attributable to the remarkable serious perturbation in the electrostatic potential. Patient 2, who exhibited the adolescence form of the disease, was found to be homozygous for a novel missense mutation c.961 T>C, p.C258R, which seemed to have minor effect on the structure of the CHS1/LYST protein. Reexamining accepted premises of missense mutant alleles being reported among patients with clinically mild forms of the disorder should be carried out, and attempts to link genotype and clinical phenotype require identifying the actual molecular effect of the mutation. Early and accurate diagnosis of the severity of the disease is extremely important to early differentiate patients who would benefit from premature enrollment into a transplantation protocol.
authors.affiliation: Centro Regional de Hemodonacion, Hospital JM Morales Meseguer, University of Murcia, Murcia, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Sánchez-Guiu
authors.forename: Ana I
authors.initials: AI
authors.lastname: Antón
authors.forename: Nuria
authors.initials: N
authors.lastname: García-Barberá
authors.forename: José
authors.initials: J
authors.lastname: Navarro-Fernández
authors.forename: Constantino
authors.initials: C
authors.lastname: Martínez
authors.forename: Jose L
authors.initials: JL
authors.lastname: Fuster
authors.forename: Jose M
authors.initials: JM
authors.lastname: Couselo
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Ortuño
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
authors.forename: Jose
authors.initials: J
authors.lastname: Rivera
authors.forename: Maria L
authors.initials: ML
authors.lastname: Lozano
mesh_terms: D000595:Amino Acid Sequence; D001853:Bone Marrow / Q000473:pathology; D002609:Chediak-Higashi Syndrome / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D006720:Homozygote; D006801:Humans; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009504:Neutrophils / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C102161:LYST protein, human; D012333:RNA, Messenger; D033921:Vesicular Transport Proteins
keywords: CHS1; Chediak-Higashi syndrome; LYST; phenotype-genotype correlation